Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Clinical and experimental evidence revealing Ph1-negative hematopoietic stem cells in the majority of chronic myelogenous leukemia (CML) patients, suggests that autologous bone marrow transplantation (ABMT) may represent a therapeutic approach for these patients. It was the aim of the present study to evaluate the efficacy of the cyclophosphamide derivative mafosfamide as a marrow purging agent in a group (n = 15) of CML patients. Chemical purging was followed by a short-term liquid culture phase supplemented with recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF). Mafosfamide (100 micrograms/ml) incubation induced a marked inhibition of progenitor cell growth, the percentages of surviving CFU-GEMM, BFU-E, and CFU-GM being 3.4, 5.4, and 4.9, respectively. At the cytogenetic level, the purging procedure failed to show any modulating effect on Ph1-negative clones in 9/15 cases. In contrast, 6/15 cases showed a significant increase in the mean (+/- SD) percentage of Ph1-negative metaphases in response to rGM-CSF (46 +/- 26, p less than or equal to 0.05), mafosfamide incubation (53 +/- 12, p less than or equal to 0.01), and the combination of mafosfamide incubation plus rGM-CSF (63 +/- 29, p less than or equal to 0.025). Immunological analysis revealed that mafosfamide incubation induced a significant enrichment of MY10 (28 +/- 9, 0.05) B73.1-positve cells (25 +/- 9, p less than or equal to 0.05). Four mafosfamide-responsive patients with CML in second chronic phase have been autografted with mafosfamide purged marrow. In all patients a Ph1-negative phase lasting 5-14 months was observed. In conclusion, it appears that (a) in a subgroup of CML patients mafosfamide purging is effective in reducing the size of the malignant clone and might induce through its cytotoxic and immune actions a modification of the balance between leukemic and normal clones, and (b) this experimental approach may be used as a screening test to select patients to undergo marrow harvest and ABMT with mafosfamide purged marrow.
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PMID:In vitro marrow purging in chronic myelogenous leukemia: effect of mafosfamide and recombinant granulocyte--macrophage colony-stimulating factor. 175 24

The results of in vivo studies conducted with colony-stimulating factors (CSFs) in autologous bone marrow transplantation (ABMT) are summarized. Our own data obtained from in vitro models dealing with the use and possible applications of CSFs in ABMT are reported. In particular, we show data concerning: 1) the use of interleukin 3, granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin 1 to expand hematopoietic progenitor cell growth in the early phase of ABMT; 2) in vitro marrow purging with Mafosfamide and GM-CSF in chronic myelogenous leukemia; and 3) growth requirements of MY10-derived leukemic colony-forming units. The use of CSFs, alone or in combination, may provide us with new strategic approaches for the treatment of acute and chronic leukemias. CSFs in combination with chemotherapeutic agents are very promising agents for purging marrow prior to ABMT.
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PMID:Hematopoietic growth factors: in vitro and in vivo studies in bone marrow transplantation. 218 39

The frequency of induced sister chromatid exchange (SCE) is a sensitive tool for the monitoring of DNA damage and has been shown to indicate chemotherapy resistance. Mafosfamide is presently used for the purging of bone marrow in autologous bone marrow transplantation in the treatment of acute leukemia. We studied the SCE-inducing effect of mafosfamide on leukemic cells of Philadelphia (Ph)-positive chronic myeloid leukemia (CML) as a model for leukemic cells. Corresponding data from normal bone marrow were analyzed for comparison. A positive linear correlation (r = 0.99, P = 0.0005) was found between the dose of mafosfamide and induced SCE in Ph-positive CML and normal bone marrow. The concentration of mafosfamide used was 0.1, 0.2, 0.4, and 0.8 micrograms/ml. Additionally, we analyzed five cases of CML and six cases of normal bone marrow. A significant difference in the frequency of induced SCE/metaphase was found between CML and normal bone marrow even after addition of 0.8 micrograms/ml mafosfamide. Also, spontaneous SCE was significantly lower in CML. Our data indicate a lower sensitivity of the leukemic cells to mafosfamide as shown by the induction of a lower frequency of SCE events.
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PMID:Mafosfamide induces less sister chromatid exchange in Ph-positive cells than in normal bone marrow. 232 26

Bone marrow purging with cyclophosphamide derivatives (Mafosfamide) requires the establishment of a defined experimental procedure for reliable leukemic cell destruction while sparing normal hematopoietic stem cells to ensure engraftment. We previously defined the granulocyte-macrophage colony-forming unit (CFU-GM) LD95 as being the maximum tolerable dose of drug to use. We now report, in 20 patients with acute non-lymphoblastic leukemia (n = 5), acute lymphoblastic leukemia (n = 5), chronic myelogenous leukemia (n = 5), and non-Hodgkin's lymphoma (n = 5), that the nature of the cells treated (i.e., buffy coat cells or mononuclear cells) significantly influences the accuracy of the LD95 determination, whereas other parameters such as hematocrit or nucleated cell concentration do not. We subsequently define the most reliable experimental procedure for in vitro purging with Mafosfamide: incubation of 2 x 10(7) buffy coat cells/ml with a hematocrit of 5%. We show that the wide individual susceptibility to the drug is not related to any incubation procedure. In a series of 163 patients with hematological malignancies, we confirm the large variation of sensitivity to the drug according to patient susceptibility and diagnosis. These data favor the adjustment of the dose of Mafosfamide on an individual basis, prior to bone marrow purging for autologous bone marrow transplantation.
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PMID:Establishment of a reliable experimental procedure for bone marrow purging with mafosfamide (ASTA Z 7557). 265 56

Bone marrow from 9 patients with Ph1+CML was treated in vitro with varying concentrations of Mafosfamide in order to test the hypothesis that selective pharmacological killing of Ph1-positive cells in CML is feasible. A marked difference in sensitivity to Mafosfamide of CFU-GM was observed, but at all concentrations 100% persistence of Ph1+ cells was noticed. We conclude that, in classical cases of Ph1-positive CML, Mafosfamide purging of bone marrow will not be effective.
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PMID:Mafosfamide (ASTA-Z-7654) in vitro treatment of bone marrow does not eradicate Philadelphia-positive cells in chronic myeloid leukaemia. 318 95

Chronic myelogenous leukemia (CML) progenitor cells have been shown to be defective in their ability to adhere to marrow stroma. It was the aim of the present study to investigate at the cytogenetic level marrow-derived CML clonogenic cells fractionated on the basis of their ability to adhere to preformed, allogeneic, normal marrow-derived stromal layers. Mononuclear marrow cells from CML patients (n = 15) were incubated with mafosfamide (100 micrograms/ml) or control medium, seeded onto marrow stromal layers and allowed to adhere (3 hrs, 37 degrees C). Following a short-term liquid culture, the different cell fractions were harvested and incorporated in methylcellulose cultures. CFU-GM grown from these cultures were analyzed by single colony karyotyping. On direct cytogenetic analysis, the overall mean (+/- SD) percentage of Ph-negative metaphases was 7 +/- 20%. Following stroma adherence and shortterm suspension culture, the mean (+/- SD) percentages of Ph-negative clones were as follows: 33 +/- 25% for adherent CFU-GM, 59 +/- 40% for adherent, mafosfamide-treated CFU-GM, 12 +/- 16% for non-adherent CFU-GM, and 32 +/- 26% for non-adherent-mafosfamide-treated CFU-GM. If only the patients showing a percentage of Ph-negative clones > or = 20% were included in this analysis, the mean (+/- SD) percentages of Ph-negative clones were 47 +/- 19% for adherent CFU-GM, and 81 +/- 21% for adherent-Mafosfamide-treated CFU-GM. In contrast, the majority of pH-positive CFU-GM were detected within the stroma non-adherent cell fraction.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Fractionation of chronic myelogenous leukemia marrow cells by stroma adherence: implications for marrow purging. 825 84